Bona fide and bystander memory B cell subsets colonize the lung peribronchial niche upon viral infection
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE174682 | GEO | 2022/06/02
REPOSITORIES: GEO
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Project description:It is unclear to what extent T helper cells with a different phenotype (chemokine receptor and cytokine production profile) are generated in response to pathogen challenge or vaccination, and whether such heterogeneity can arise among the progeny of a single precursor. We combined cellular methods to isolate antigen specific T cells from different T helper memory subsets of human donors, and next generation sequencing of their TCR. This approach revealed a high level of heterogeneity in the phenotype of human T cells responding to different pathogens/vaccines also at a clonal level, as we could characterize cells bearing an identical T cell receptor with divergent effector properties. NGS-based analysis of T cell receptor repertoire of T helper memory cells identical gross specificity (i.e. responding to a given pathogen or vaccine antigen) belonging to different heper subsets (Th1, Th2, Th17)
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Project description:Bacterial regulatory RNAs have been extensively studied for over a decade, and are progressively being integrated into the complex genetic regulatory network. Transcriptomic arrays, recent deep-sequencing data and bioinformatics suggest that bacterial genomes produce hundreds of regulatory RNAs. However, while some have been authenticated, the existence of the others varies according to strains and growth conditions, and their detection fluctuates with the methodologies used for data acquisition and interpretation. For example, several small RNA (sRNA) candidates are now known to be parts of UTR transcripts. Accurate annotation of regulatory RNAs is a complex task essential for molecular and functional studies. We defined bona fide sRNAs as those that (i) likely act in trans and (ii) are not expressed from the opposite strand of a coding gene. Using published data and our own RNA-seq data, we reviewed hundreds of Staphylococcus aureus putative regulatory RNAs using the DETR'PROK computational pipeline and visual inspection of expression data, addressing the question of which transcriptional signals correspond to sRNAs. We conclude that the model strain HG003, a NCTC8325 derivative commonly used for S. aureus genetic regulation studies, has only about 50 bona fide sRNAs, indicating that these RNAs are less numerous than commonly stated. Among them, about half are associated to the S. aureus sp. core genome and a quarter are possibly expressed in other Staphylococci. We hypothesize on their features and regulation using bioinformatic approaches.
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Project description:Mammalian prions are PrP proteins with altered structures causing transmissible fatal neurodegenerative diseases. They are self-perpetuating through formation of beta-sheet-rich assemblies that seed conformational change of cellular PrP. Pathological PrP usually forms an insoluble protease-resistant core exhibiting beta-sheet structures but no more alpha-helical content, loosing the three alpha-helices contained in the correctly folded PrP. The lack of a high-resolution prion structure makes it difficult to understand the dynamics of conversion and to identify elements of the protein involved in this process. To determine whether completeness of residues within the protease-resistant domain is required for prions, we performed serial deletions in the helix H2 C terminus of ovine PrP, since this region has previously shown some tolerance to sequence changes without preventing prion replication. Deletions of either four or five residues essentially preserved the overall PrP structure and mutant PrP expressed in RK13 cells were efficiently converted into bona fide prions upon challenge by three different prion strains. Remarkably, deletions in PrP facilitated the replication of two strains that otherwise do not replicate in this cellular context. Prions with internal deletion were self-propagating and de novo infectious for naive homologous and wild-type PrP-expressing cells. Moreover, they caused transmissible spongiform encephalopathies in mice, with similar biochemical signatures and neuropathologies other than the original strains. Prion convertibility and transfer of strain-specific information are thus preserved despite shortening of an alpha-helix in PrP and removal of residues within prions. These findings provide new insights into sequence/structure/infectivity relationship for prions.Prions are misfolded PrP proteins that convert the normal protein into a replicate of their own abnormal form. They are responsible for invariably fatal neurodegenerative disorders. Other aggregation-prone proteins appear to have a prion-like mode of expansion in brains, such as in Alzheimer's or Parkinson's diseases. To date, the resolution of prion structure remains elusive. Thus, to genetically define the landscape of regions critical for prion conversion, we tested the effect of short deletions. We found that, surprisingly, removal of a portion of PrP, the C terminus of alpha-helix H2, did not hamper prion formation but generated infectious agents with an internal deletion that showed characteristics essentially similar to those of original infecting strains. Thus, we demonstrate that completeness of the residues inside prions is not necessary for maintaining infectivity and the main strain-specific information, while reporting one of the few if not the only bona fide prions with an internal deletion.
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Project description:Extracorporeal photochemotherapy (ECP) is employed for the management of cutaneous T cell lymphoma (CTCL). ECP involves the extracorporeal exposure of white blood cells (WBCs) to a photosensitizer, 8-methoxypsoralen (8-MOP), in the context of ultraviolet A (UVA) radiation, followed by WBC reinfusion. Historically, the therapeutic activity of ECP has been attributed to selective cytotoxicity on circulating CTCL cells. However, only a fraction of WBCs is exposed to ECP, and 8-MOP is inactive in the absence of UVA light, implying that other mechanisms underlie the anticancer effects of ECP. Recently, ECP has been shown to enable the physiological differentiation of monocytes into dendritic cells (DCs) that efficiently cross-present tumor-associated antigens (TAAs) to CD8+ T lymphocytes to initiate cognate immunity. However, the source of TAAs and immunostimulatory signals for such DCs remains to be elucidated. Here, we demonstrate that 8-MOP plus UVA light reduces melanoma cell viability along with the emission of ICD-associated danger signals including calreticulin (CALR) exposure on the cell surface and secretion of ATP, high mobility group box 1 (HMGB1) and type I interferon (IFN). Consistently, melanoma cells succumbing to 8-MOP plus UVA irradiation are efficiently engulfed by monocytes, ultimately leading to cross-priming of CD8+ T cells against cancer. Moreover, malignant cells killed by 8-MOP plus UVA irradiation in vitro vaccinate syngeneic immunocompetent mice against living cancer cells of the same type, and such a protection is lost when cancer cells are depleted of calreticulin or HMGB1, as well as in the presence of an ATP-degrading enzyme or antibodies blocking type I IFN receptors. ECP induces bona fide ICD, hence simultaneously providing monocytes with abundant amounts of TAAs and immunostimulatory signals that are sufficient to initiate cognate anticancer immunity.
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Project description:It is known that the DnaK and Trigger Factor (TF) chaperones cooperate in the folding of newly synthesized cytosolic proteins in Escherichia coli. We recently showed that despite a very narrow temperature range of growth and high levels of aggregated cytosolic proteins, E. coli can tolerate deletion of both chaperones, suggesting that other chaperones might be involved in this process. Here, we show that the secretion-dedicated chaperone SecB efficiently suppresses both the temperature sensitivity and the aggregation-prone phenotypes of a strain lacking both TF and DnaK. SecB suppression is independent of a productive interaction with the SecA subunit of the translocon. Furthermore, in vitro cross-linking experiments demonstrate that SecB can interact both co- and posttranslationally with short nascent chains of both secretory and cytosolic proteins. Finally, we show that such cotranslational substrate recognition by SecB is greatly suppressed in the presence of ribosome-bound TF, but not by DnaK. Taken together, our data demonstrate that SecB acts as a bona fide generalized chaperone.
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Project description:Cl- is the major extracellular (Cl-out) and intracellular (Cl-in) anion whose concentration is actively regulated by multiple transporters. These transporters generate Cl- gradients across the plasma membrane and between the cytoplasm and intracellular organelles. [Cl-]in changes rapidly in response to cell stimulation and influences many physiological functions, as well as cellular and systemic homeostasis. However, less appreciated is the signaling function of Cl-. Cl- interacts with multiple proteins to directly modify their activity. This review highlights the signaling function of Cl- and argues that Cl- is a bona fide signaling ion, a function deserving extensive exploration.
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Project description:The current optogenetic toolkit lacks a robust single-component Ca2+-selective ion channel tailored for remote control of Ca2+ signaling in mammals. Existing tools are either derived from engineered channelrhodopsin variants without strict Ca2+ selectivity or based on the stromal interaction molecule 1 (STIM1) that might crosstalk with other targets. Here, we describe the design of a light-operated Ca2+ channel (designated LOCa) by inserting a plant-derived photosensory module into the intracellular loop of an engineered ORAI1 channel. LOCa displays biophysical features reminiscent of the ORAI1 channel, which enables precise optical control over Ca2+ signals and hallmark Ca2+-dependent physiological responses. Furthermore, we demonstrate the use of LOCa to modulate aberrant hematopoietic stem cell self-renewal, transcriptional programming, cell suicide, as well as neurodegeneration in a Drosophila model of amyloidosis.
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Project description:Antigen recognition by CD8+ naïve T cells induces immune activation and rapid effector differentiation that ensures elimination of virally-infected and malignant cells. While signals from the extracellular milieu and downstream of the TCR have long been known to play a crucial role, it is currently unknown whether heterogeneity within the naïve CD8+ T cell pool shapes the potency of effector differentiation. We report the identification of two discrete subsets of human CD8+ TN cells, defined by positive and negative expression of the chemokine receptor CXCR3, with different potential to generate fully-differentiated effector T cells following antigen-specific stimulation. The CXCR3+ are more abundant than the CXCR3– naïve in peripheral blood and lymphoid tissues, retain enhanced expression of effector-related genes ex vivo and display features of the T cell receptor chain repertoire indicating enhanced capacity to bind the peptide:major histocompatibility complex. Likewise, a phenotypically equivalent murine CD8+ naïve population expressing high levels of CD5, a surrogate indicator of enhanced TCR sensitivity for self, preferentially generates short-lived effector cells following infection. Our findings imply that CD8+ T cell effector differentiation potential in humans is shaped by heterogeneity in the preimmune repertoire
2019-10-17 | GSE125100 | GEO
Project description:Antigen recognition by CD8+ naïve T cells induces immune activation and rapid effector differentiation that ensures elimination of virally-infected and malignant cells. While signals from the extracellular milieu and downstream of the TCR have long been known to play a crucial role, it is currently unknown whether heterogeneity within the naïve CD8+ T cell pool shapes the potency of effector differentiation. We report the identification of two discrete subsets of human CD8+ TN cells, defined by positive and negative expression of the chemokine receptor CXCR3, with different potential to generate fully-differentiated effector T cells following antigen-specific stimulation. The CXCR3+ are more abundant than the CXCR3– naïve in peripheral blood and lymphoid tissues, retain enhanced expression of effector-related genes ex vivo and display features of the T cell receptor chain repertoire indicating enhanced capacity to bind the peptide:major histocompatibility complex. Likewise, a phenotypically equivalent murine CD8+ naïve population expressing high levels of CD5, a surrogate indicator of enhanced TCR sensitivity for self, preferentially generates short-lived effector cells following infection. Our findings imply that CD8+ T cell effector differentiation potential in humans is shaped by heterogeneity in the preimmune repertoire
2019-10-17 | GSE125099 | GEO
Project description:Manipulation of the ubiquitin proteasome system (UPS) is emerging as a common theme in viral pathogenesis. Some viruses have been shown to encode functional homologs of UPS enzymes, suggesting that a systematic identification of these products may provide new insights into virus-host cell interactions. Ubiquitin-specific proteases, collectively known as deubiquitinating enzymes (DUBs), regulate the activity of the UPS by hydrolyzing ubiquitin peptide or isopeptide bonds. The prediction of viral DUBs based on sequence similarity with known enzymes is hampered by the diversity of viral genomes. In this study sequence alignments, pattern searches, and hidden Markov models were developed for the conserved C- and H-boxes of the known DUB families and used to search the open reading frames (ORFs) of Epstein-Barr virus (EBV), a large gammaherpesvirus that has been implicated in the pathogenesis of a broad spectrum of human malignancies of lymphoid and epithelial cell origin. The searches identified a limited number of EBV ORFs that contain putative DUB catalytic domains. DUB activity was confirmed by functional assays and mutation analysis for three high scoring candidates, supporting the usefulness of this bioinformatics approach in predicting distant homologues of cellular enzymes.
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